IE73200B1 - Octadecyl-[2-(N-methylpiperidino)-ethyl]-phosphate and a process for its preparation - Google Patents
Octadecyl-[2-(N-methylpiperidino)-ethyl]-phosphate and a process for its preparationInfo
- Publication number
- IE73200B1 IE73200B1 IE922183A IE922183A IE73200B1 IE 73200 B1 IE73200 B1 IE 73200B1 IE 922183 A IE922183 A IE 922183A IE 922183 A IE922183 A IE 922183A IE 73200 B1 IE73200 B1 IE 73200B1
- Authority
- IE
- Ireland
- Prior art keywords
- octadecyl
- phosphate
- ethyl
- methylpiperidino
- compound
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- CUQJLYFFQBHUGW-UHFFFAOYSA-N 2-(1-methylpiperidin-1-ium-1-yl)ethyl octadecyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+]1(C)CCCCC1 CUQJLYFFQBHUGW-UHFFFAOYSA-N 0.000 title claims description 16
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 31
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 24
- -1 piperidine compound Chemical class 0.000 claims description 24
- 150000002500 ions Chemical class 0.000 claims description 19
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 11
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
- 239000010452 phosphate Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000013543 active substance Substances 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910052740 iodine Chemical group 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 239000011630 iodine Chemical group 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 239000012050 conventional carrier Substances 0.000 claims 1
- 239000012059 conventional drug carrier Substances 0.000 claims 1
- 150000005690 diesters Chemical class 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 13
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
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- 238000010992 reflux Methods 0.000 description 6
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
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- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 2
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- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- WPPONCHFOIIFIJ-UHFFFAOYSA-N N1N=NN=[C-]1 Chemical compound N1N=NN=[C-]1 WPPONCHFOIIFIJ-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- QDUXDCXILAPLAG-UHFFFAOYSA-N hydron;1-methylpiperidine;chloride Chemical compound Cl.CN1CCCCC1 QDUXDCXILAPLAG-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- ZBNJXSZNWZUYCI-UHFFFAOYSA-N octadecyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C ZBNJXSZNWZUYCI-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- JUYUYCIJACTHMK-UHFFFAOYSA-N quinoline-8-sulfonyl chloride Chemical compound C1=CN=C2C(S(=O)(=O)Cl)=CC=CC2=C1 JUYUYCIJACTHMK-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
- Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)
Abstract
Octadecyl 2-(N-methylpiperidino)ethyl phosphate, the use thereof in pharmaceutical compositions, in particular with an antineoplastic action, and process for the preparation thereof.
Description
ORGANISED UNDER THE LAWS OF GERMANY, OF WEISMiiLLERSTRASSE 45, D-6000 FRANKFURT AM MAIN 1, GERMANY.
(C) Copyright 1997, Government of Ireland.
Octadecvl-Γ2-(N-methvlpiperidino)-ethvll-phosphate and a process for its preparation European patent application 108,565 relates to compounds of 5 general formula O R2 l N +/ 3 R1 (0) n-P-OCH,CH,N-R3 I. \4 O R4 and their pharmaceutically acceptable salts where Rx is an aliphatic hydrocarbon radical with 8-30 carbon atoms, the radicals R2, R3 and R4 are the same or different and are hydrogen or lower alkyl radicals or where the group NR2R3R4 represents a cyclic ammonium group and n has the values 0 or 1. These compounds are said to have an anti-tumour effect and a fungus-inhibiting effect.
The invention relates to octadecyl-[2-(N-methylpiperidino)ethyl]-phosphate, processes for its preparation and medicaments containing this compound as active substance. The compound of the invention surprisingly has a very much better or more advantageous anti-tumour effect than the compounds described or mentioned in European application 108,565.
In addition, the compounds of the invention cause inhibition of blood platelet aggregation and, in addition, have a phospholipase-A2-inhibiting and lipoxygenase-inhibiting effect.
The invention also relates to a new, improved method of preparation and working up of octadecyl-[2-(Nmethylpiperidino)-ethyl]-phosphate (process a).
It has surprisingly been found that the process of the invention achieves a higher total yield and a purer product, although one less purification step is used than in the previously known process for alkylphosphocholines. What is more, less solvent is used here. The new process of the invention also avoids the use of alkylating reagents such as dimethyl sulphate which lead, through the use of potassium carbonate as an auxiliary base, to an excessively high potassium content of the product. The potassium content must be kept as low as possible in substances used as pharmaceutically active substances.
In addition the time-consuming chromatography step is no longer needed for purification purposes.
The product purity achieved according to the new process is higher than in the known process for the preparation of alkylphosphocholines, and in addition it produces higher yields (in particular in larger-scale preparation).
The first step of process a) consists in reacting phosphorus oxychloride with N-octadecyl alcohol optionally in the presence of halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons with 5 to 10 carbon atoms, liquid aromatic hydrocarbons which may also be substituted by halogen (in particular chlorine) or mixtures of the above mentioned solvents, optionally in the presence of a basic substance conventionally used herefor.
Halogenated hydrocarbons that may for example be used are hydrocarbons with 1 to 6 carbon atoms where one or several or all hydrogen atoms are replaced by chlorine atoms. It is for example possible to use methylene chloride, chloroform, ethylene chloride, chlorobenzene, dichlorobenzene. If a halogen-substituted aromatic hydrocarbon is used, these are preferably substituted with one or two halogen atoms.
Saturated cyclic ethers that may be used are for example ethers with a ring size of 5-6 which consist of carbon atoms and one or two oxygen atoms.
Examples thereof are tetrahydrofuran, dioxan.
The acyclic ethers consist of 2 to 8 carbon atoms and are liquid.
The following may for example be used: diethyl ether, diisobutyl ether, methyl-tert.-butyl ether, diisopropyl ether.
Saturated hydrocarbons that may be considered are unbranched and branched hydrocarbons which consist of 5 to 10 carbon atoms and are liquid. Pentane, hexane, heptane, cyclohexane may for example be considered.
Aromatic hydrocarbons that may for example be considered are benzene and alkyl-substituted benzenes, where the alkyl substituents consist of 1 to 5 carbon atoms.
Basic substances that may be considered both for the reaction of phosphorus oxychloride with the n-octadecyl alcohol and also for the subsequent reaction with the n-methyl-piperidinoethanol salt are amines, for example aliphatic amines of formula NR^RjI^, where Rlr R2 and R3 are the same or different and represent hydrogen or C^-Cg-alkyl or also aromatic amines such as pyridine, picoline, quinoline.
For the reaction with the N-methyl-piperidino-ethanol salt it is possible to add the basic substance required herefor at the same time or also before the N-methyl-piperidino-ethanol salt. For this reaction a solvent is needed in any case; in other words if the first reaction step is conducted without a special solvent, one has to be added at this stage. The Mol ratio of phosphorus oxychloride to the octadecyl alcohol is for example between 1.5:1 to 1:1.
The N-methyl-piperidino-ethanol salt is for example used in excess in relation to the n-octadecyl alcohol (about l.l - 1.5 molar excess).
If the reaction of the phosphorous oxychloride with the n-octadecyl alcohol occurs in the presence of a basic substance, the amount of the basic substance is for example 1 to 3 Mol related to 1 Mol POC13. For the subsequent reaction with the piperidine salt 1 the amount of basic substance used is for example 1 to 5 Mol related to 1 Mol alkanol.
The reaction temperature of the reaction of phosphorus oxychloride with n-octadecyl alcohol is between -30°C and +30°C, preferably -15°C and +5°C, in particular -10°C and -5°C.
The reaction time of this reaction is for example 0.5 - 5 hours, preferably 1-3 hours, in particular 1.5 - 2 hours. If the reaction occurs in the presence of a basic substance, it generally takes place quickly (about 30 minutes).
The piperidine salt is then added in portions or completely. Salts of N-methyl-piperidine-ethanol that may be considered are salts with mineral acids, (such as sulphuric acid, hydrochloric acid) as well as salts with organic acids such as acetic acid, para-toluenesulphonic acid and the like.
This reaction step occurs in an inert solvent. Solvents that may be used here are the same that are used for the reaction of the phosphorus oxychloride with the n-octadecyl alcohol, if this reaction occurs in a solvent.
The basic substance is then dissolved in one of the stated solvents, or a solvent is added dropwise.
Solvents for the basic substance that are preferably used here are: halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons with 5 to 10 carbon atoms, liquid aromatic hydrocarbons or mixtures of the above mentioned solvents.
These are the same solvents that may be used for the reaction of the phosphorus oxychloride with the n-octadecyl alcohol. 1 piperidine salt always means N-methyl-piperidinoethanol salt Addition of the basic substance causes the temperature to rise.
Care should be taken to ensure that the temperature is maintained in a range between 0°C and 40°C, preferably 10°C to 30°C, in particular to 15°C to 20°C.
The reaction mixture is then stirred at 5°C to 3 0°C, preferably 15°C and 25°C (for example 1 hour to 40 hours, preferably 3 hours to 15 hours).
The hydrolysis of the reaction batch occurs by addition of water, it being necessary to maintain a temperature between 10°C and 30°C, preferably 15°C and 30°C, in particular between 15°C and 20°C.
The previously mentioned hydrolysis liquids may also contain basic substances. Basic substances of this kind that may be considered are carbonates and hydrogen carbonates of alkali and alkaline earth metals.
To complete the hydrolysis the mixture is then stirred for a further 0.5 hours to 4 hours, preferably 1 to 3 hours, in particular 1.5 to 2.5 hours at 10°C to 30°C, preferably at 15°C to 25°C, in particular at 18°C to 22°C.
The reaction solution is then washed with a mixture of water and alcohols (preferably aliphatically saturated alcohols with 1 to 4 carbon atoms) which may optionally also contain a basic substance.
The mixing ratio water: alcohol may for example be between 5 and 0.5, preferably 1-3 (V/V).
Basic substances for the washing liquid that may for example be considered are carbonates and hydrogen carbonates of alkali and alkaline earth metals as well as ammonia (for example aqueous ammonia). A 3% sodium carbonate solution in water is particularly preferred.
It is subsequently optionally possible to wash the reaction solution with an acid solution.
Acid washing is advantageous to remove as yet unreacted basic constituents of the reaction solution, particularly when methylene chloride is used as solvent.
The washing solution consists of a mixture of water and alcohols. Mixtures of aliphatically saturated alcohols with 1 to 4 carbon atoms are preferably used, it optionally also being possible for an acid substance to be present. The mixing ratio water:alcohol may for example be between 5 and 0.5, preferably 1-3 (V/V).
Acid substances that may for example be used as the washing liquid are for example mineral acids and organic acids, for example hydrochloric acid, sulphuric acid or tartaric acid, and citric acid. A 10% solution of hydrochloric acid in water is particularly preferred.
The mixture is then washed once more with a mixture of water and alcohols. Mixtures of aliphatically saturated alcohols with 1 to 4 carbon atoms are preferably used, it optionally being possible for a basic substance also to be present.
The mixing ratio water: alcohol may for example be between 5 and 0.5, preferably 1-3.
The washed phases are then combined and dried in the conventional manner and then the solvent is removed (preferably under reduced pressure, for example 5 to 100 mbar) optionally after addition of 150 - 1000 ml, preferably 300 - 700 ml, in particular 450 - 550 ml of an aliphatic alcohol (related to 1 Mol part by weight of dried product) . The alcohols that may advantageously be considered are saturated aliphatic alcohols with a chain length of 1 and 5 carbon atoms. This alcohol treatment is designed to remove residual water completely.
The product obtained in this manner may be purified in the conventional way (e.g. by chromatography, recrystallization).
The following, also inventive, purification process is, however, particularly preferred: The solid residue as described above is for example suspended in saturated aliphatic ketones (3-6 carbon atoms), for example acetone, butanone, methyl-tert.-butyl ketone, stirred for 1 to 4 hours, preferably 2 hours, suction filtered and dried at 20°C to 50°C in a vacuum at 5 Torr to 100 Torr.
The product pre-purified in this manner is taken up in anhydrous alcohols (Cx to C4) or in alcohols containing a maximum of 5 % by weight of water at 20°c to 60°C, preferably 40°C and insoluble constituents filtered off. Alcohols that may for example be used are methanol, ethanol, isopropanol, butanol, isobutanol. The filtrate obtained is then stirred with a mixed-bed ion exchanger, for example AmberliteR MB3 for example for 1 to 5 hours, preferably 2 hours, at 10°C to 50°C, preferably 20°C.
Instead of a mixed-bed ion exchanger it is also possible for purification to be effected successively with an acid ion exchanger and a basic ion exchanger.
Ion exchangers that may be used are all insoluble solids that contain ion-exchanging groups.
Acid ion exchangers are those which contain for example acid groups such as sulphonic acid groups, carboxyl groups. Examples are ion exchangers with sulphonic acid groups in a polystyrene matrix such as AmberliteR IR 120, DowexR HCR, DuoliteR C 20 or LewatitR S 100. Weakly acid ion exchangers are for example those base on a polyacrylic acid matrix, such as AmberliteR IRC 76, DuoliteR C 433 or ReliteR CC.
Basic ion exchangers that may for example be considered are those having on a polymer matrix (e.g. polystyrene matrix) primary, secondary, tertiary or quaternary amino groups such as Duolite* A 101, DuoliteR A 102, DuoliteR15 A 348, Duolite* A 365, DuoliteR A 375, AmberliteR IRA 67, DuoliteR A 375, AmberliteR IRA 458 and DuoliteR A 132.
Mixed-bed ion exchangers are mixtures of acid and alkaline ion exchanger resins, such as AmberliteR MB1, AmberliteR MB2, AmberliteR MB3 and AmberliteR MB6.
Other ion exchangers that may be used are listed in Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition (1989), Volume A14, p. 450.
Following suction filtering of the ion exchanger resin the mixture is evaporated under reduced pressure (for example 20 Torr to 200 Torr) at 40°C to 70°C and the mixture is then recrystallized from halogenated hydrocarbons, saturated aliphatic ketones or from alcohol/ketone mixtures.
Halogenated hydrocarbons that may for example be considered for the recrystallization are hydrocarbons containing 1 to 6 carbon atoms where one or several or all carbon atoms are replaced by chlorine atoms.
It is for example possible to use methylene chloride, chloroform, ethylene chloride, chlorobenzene.
Alcohols that may be considered are saturated aliphatic alcohols with 1 to 6 carbon atoms and 1 to 3 hydroxyl groups. Ketones that may be considered are saturated, aliphatic ketones with 3 to 6 carbon atoms.
The mixing ratio alcohol:ketone is 1 to 1-5 (volume/volume).
An ethanol/acetone mixture in the ratio of 1:1 (V/V) is specially preferred.
The crystals of octadecyl-[2-(N-methyl-piperidino)-ethanol phosphate obtained are suction filtered and if necessary washed for example washed with saturated hydrocarbons containing 1 to carbon atoms. (Temperature of the washing liquid for example to 30°C).
It is also possible to obtain the compound of the invention by reacting in known manner b) a compound of formula C18H37-O-PO(°H) 2 1 or a reactable derivative of this compound with a compound of formula Z II optionally in the presence of basic substances, where Z represents hydrogen, methyl or the group -CH2-CH2-OH and the piperidine compound may also be present in the form of the N-methy1-piperidinium derivative, where in this case the positive charge is neutralized by the anion of an inorganic or organic acid and optionally methylated, or c) a compound of the formula C18H37"O-P°(°H) °"CH2CH2Y 111 where Y is chlorine, bromine or iodine is reacted with piperidine or N-methyl-piperidine and optionally methylated or d) a compound of the general formula ci8h37~o-po (°h) -o-ch2-ch2-N\ y is methylated or a compound obtained according to b) or c) is methylated.
With regard to process b): The process b) may be carried out without solvent (in this case excess of compound II) or in an inert solvent at temperatures between 0 and 180°C, preferably 18 - 120°C. Solvents that are for example suitable are: lower aliphatic alcohols (methanol), aliphatic straight-chain ethers (diethyl ether), saturated cyclic ethers (dioxan, tetrahydrofuran), aromatic hydrocarbons (toluene, benzene, pyridine), chlorinated aliphatic lower molecular hydrocarbons (CHC13, CC14), lower alkyl amides or dialkyl amides of lower molecular aliphatic carboxylic acids (dimethyl formamide, dimethyl acetamide) or also dimethyl sulphoxide, acetonitrile. The working up is carried out in known manner by hydrolysis using alcohols/water or water alone. Purification of the reaction product is effected for example by recrystallization or column chromatography. The reaction according to process b) can also be conducted in the presence of additional basic substances such as tertiary amines (N-methyl piperidine, N-methyl morpholine, N-methyl pyrolidine, quinoline, pyridine).
If the starting compound is the free acid C18H37-O-PO(OH) 2, this is activated by known condensation agents such as 2,4,6-trimethylbenzene sulphonyl chloride, 8-quinoline sulphonyl chloride, 2,4,6-isopropylbenzene sulphonyl imidazolide, 2,4,6-trimethylbenzene sulphonyl tetrazolide or dicyclohexyl carbodiimide and then reacted.
If the starting compound C18H37-O-PO(OH) 2 is present in the form of an activated derivative, this is for example compounds where both OH groups are substituted by halogen (Cl, Br, I).
The activated derivative used may for example also be a compound of formula in which case the reaction is preferably carried out in an autoclave or a stirring apparatus at a temperature between -20 to 130°C.
If the starting compound of formula II is used as a piperidinium salt, the acid ions that may be considered are: Cl, Br-, I", tosylate anion, sulphuric acid anion (HSO4", SO22-) .
With regard to process c): This reaction is conducted in known manner without solvent or in an inert solvent at temperatures between 50 to 100°C.
The solvents that may be considered are the same as for process b) : the piperidine or N-methyl-piperidine may also act in excess as solvent.
The reaction is appropriately carried out in the presence of acid-binding (halide-binding) substances such as Ag2CO3.
With regard to process d): The alkylation is for example conducted by reaction with compounds of formula MHal, AsSO2OM and SO2(OM)2, where Hal is a halogen atom (in particular chlorine, bromine or iodine) and Ar is an aromatic radical (for example a phenyl or naphthyl radical optionally substituted by one or several lower alkyl radicals and M is the methyl radical. Examples are p-toluene sulphonic acid methyl ester, dimethyl sulphate, methyl halides. The alkylation reaction is optionally carried out with addition of conventional acid-binding agents, such as alkali hydroxides, alkali carbonates, alkali hydrogen carbonates, alkaline earth carbonates, alkali acetates, tertiary amines (for example trialkyl amines such as triethylamine), pyridine or also alkali hydrides at temperatures between 0 and 200°C, preferably 40 and 140°C in inert solvents or suspension agents. Solvents and dispersing agents that may for example be considered are: aromatic hydrocarbons such as benzene, toluene, xylene; aliphatic ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; aliphatic ethers such as butyl ether; cyclic ethers such as tetrahydrofuran, dioxan; sulphoxides such as dimethyl sulphoxide; tertiary acid amides such as dimethyl formamide, N-methyl pyrrolidone, hexamethylphosphoric acid triamide; aliphatic alcohols such as methanol, ethanol, isopropanol, amyl alcohol, tert.-butanol, cycloaliphatic hydrocarbons such as cyclohexane and the like. It is also possible to use aqueous mixtures of the solvents mentioned. Working is frequently at the reflux temperature of the solvents or dispersing agents used.
The alkylation reaction components are frequently used in excess. The alkylation may also be conducted in the presence of tetraalkyl ammonium salts (in particular the halides) in combination with alkali hydroxides at temperatures between 0 100°C, preferably 20 - 80°C in an aprotic solvent or also in chloroform or methylene chloride. Aprotic solvents that may in particular be considered are: tertiary amides (dimethyl formamide, N-methyl pyrrolidone, dimethyl sulphoxide, acetonitrile, dimethoxyethane, acetone, tetrahydrofuran.
The alkylation may optionally also be conducted by first preparing an alkali compound (sodium salt, potassium salt or also lithium salt for example) from the compound to be alkylated by reacting it in an inert solvent such as dioxan, dimethyl formamide, benzene or toluene with an alkali metal, alkali hydride or alkali amides (in particular sodium or sodium compounds) or butyl lithium at temperatures between 0 and 150°C and then adding the alkylizing agent.
Instead of the listed alkylizing agents it is also possible to use other chemical equivalent agents conventionally used in chemistry (see for example also L.F. and Mary Fieser Reagents for Organic Synthesis, John Wiley and Sons. In., New York, 1967, Vol. l, pages 1303-4 and Vol. 2 page 471).
The growth inhibition index WHI is determined in the human KB tumour cell line which is transplanted in nude mice. The growth inhibition index is defined as follows: WHI = Mcontrol - Mtreatment_ x 100 % Mcontrol of the treated group or in the control group on the 14th day after treatment related to the value on the day of application. A WHI greater than 100 % means that the tumours have become smaller due to the treatment; a WHI smaller than 100%, in contrast, only shows a treatment-related slowing down in tumour growth as compared to the controls. In other words, the higher the WHI, the stronger the antitumour efficacy of a test substance.
The EC90 is determined in vitro in the same cell line. The EC90 is the concentration of substance having an antitumour effect in Mg/ml which inhibits the growth of cancer cells in vitro by 90 % in comparison to a control experiment without addition of the antitumour-acting substance.
The Cape Index (coefficient for cancer-inhibiting effects) is a measure for the high selectivity and specificity of a chemical substance vis-a-vis antitumour-acting substances. This Cape index is obtained by dividing the WHI index by the EC90 index.
This means that an effect in the animal (in vivo) is compared to the effect in an in vitro system. It has been found that the higher the coefficient formed in this manner, the more selective and effective the antitumour effect of a substance is.
The compounds of the invention display a good anti-neoplastic 10 effect in the KB tumour (human carcinoma of the buccal cavity, transplanted subcutaneously to nude mice) and in autochthonous, chemically-induced DMBA-breast gland cancer in the rat.
For example a dose of 2 x 316 mg/kg body weight of the compound of the invention, given at intervals of one week, achieved a regression of the KB tumours.
After a 14-day oral treatment with an oral dose of 21.5 mg/kg body weight of the compound of the invention daily, DMBA tumours weighing 5 g regressed to the borderline of palpability.
As shown in Table 1, the compound of the invention therefore has an antitumour efficacy that is higher and more specific by a multiple factor as compared to the compounds of similar structure. This effect was not obvious.
Table 1 Substance Growth inhibition index WHI in % in vivo/ humane KB tumor Cell line transplanted into nude mice ECgo in gg/ml Human KB tumor cell line in vitro Cape-Index © cleH37-A-t0 ch3 D 20133, compound of the invention 121 0,3 403 Compounds of similar structure Φ C19H39-A-nQ> ch3 D 21545 13,7 1,3 10 © C20H4l"A~yQ^ ch3 D 21033 7 0,3 23 A = o-po-o-ch2-ch20 Φ C22H45~A~^( ch3 D 21052 0 3,2 0 Φ Cl,H35-A-ljQ 1 ch3 D 20813 76 2 38 Φ Cl6H33-A-lO ch3 D 20317 38 1,4 27 © C18H37-A-lQ H D 20110 25 1 25 Φ Ci8H37-A-JjO c2h5 D 20931 13 1 13 Φ c18h37-a-nQo ch3 D 20680 0 >10 0 C18H37-A-nQ> D 19862 0 > 1 0 Φ Ci8H37-A-N(CH3)3 D 19391 11 0,31 36 © C18H37-A-lQ ch3 D 20918 0 1 0 ®/=" c18h37-a-n^ D 20706 0 3,1 0 0 Φ V. NH C^H^-A-NH^^ F 20 10 2 Example 1 Preparation according to the new process (process a) » Octadeeyl-Γ 2-(N-roethvlpiperidino)-ethyl1-phosphate_(number D—20133) 9.2 ml (0.1 Mol) POCl3 in 50 ml chloroform are added to a stirring apparatus under nitrogen and cooled in an ice bath to 5°C. 24.3 g (0.09 Mol) octadecanol are dissolved in 100 ml chloroform under light heating and added dropwise together with 32 ml (0.40 Mol) pyridine at a temperature of 5 - 12°C. Dropping time: 30 minutes. After post-stirring for half an hour 37.9 (0.12 Mol) solid 2-(N-methyl-piperidino)-ethanol tosylate are added and then 40 ml pyridine are added dropwise. This causes the temperature to rise to 15°C. The ice bath is removed and the reaction mixture is stirred for 2.5 hours at room temperature. For purposes of hydrolysis 15 ml water are added dropwise within 10 minutes. After stirring for half an hour, the reaction solution is washed in each case once with 200 ml water/methanol (1:1), 200 ml 3 percent Na2CO3/methanol (1:1) and 200 ml water/methanol (1:1). The reaction solution washed in this manner is dried over Na2SO4 and evaporated in a rotary evaporator in a vacuum after addition of a little i-propanol.
The residue is recrystallized from 200 ml butanone. The wax-like product formed is filtered off and dissolved with heat in 150 ml 96% ethanol. The precipitate is filtered off and the filtrate is cooled in the refrigerator for four hours.
The precipitate is filtered off again and the filtrate mixed with 85 g Amberlite* MB3. After stirring for three hours, the ion exchanger is removed and the solution evaporated in a rotary evaporator in a vacuum. The residue is recrystallized from 150 ml butanone followed by drying in a vacuum over phosphorus pentoxide.
Yield: 21.7 g (45.6 mmol, 51 %).
MP 113 °C Rf-value: 0.53 (thin layer chromatogram in silica gel, mobile phase methylene chloride/methanol/25 percent ammonia 80:25:5.
The starting -N-methy 1-piperidino compound may for example be prepared in the following manner: 64.59 g (0.50 mol) 2-piperidinoethanol are dissolved in 125 ml acetonitrile and mixed dropwise with cooling with a solution of 93.1 g (0.50 mol) 4-toluene sulphonic acid methyl ester in 125 ml acetonitrile within 30 minutes. The mixture is stirred for half an hour each at room temperature and under reflux. After cooling the solvent is removed in a vacuum and the residual oil is dissolved in 200 ml hot acetone. The product precipitates in crystalline form on cooling. The crystallization is completed in the ice compartment. After suction filtering the result is post-washed with acetone and dried at 4 0°C over P2O5a vacuum.
Yield: 139 g (0.45 mol, 90%) 2-hydroxyethyl-N-methyl piperidinium tosylate.
Example 2 Preparation according to process c) Octadecvl-r2-(N-methvl piperidino)-ethyl1-phosphate (number D-20133) .0 g (44.0 ml) octadecyl-2-bromoethyl phosphate and 73 ml (600 mmol) N-methyl piperidine are heated under reflux for 3 hours. After cooling the result is evaporated, the residue taken up in 120 ml methanol and boiled for three hours under reflux after addition of 17.9 g (62.0 mmol) Ag2CO3. The reaction mixture is filtered hot over a membrane filter and concentrated. The residue is dissolved in 25 ml CHCl3/methanol/25 percent NH4OH (80:25:5) and filtered over a layer of silica gel. The filtrate is evaporated, the residue is stirred with acetone and suction filtered. The product is dissolved in a little CH2Cl2 and precipitated with acetone.
Yield: 3.50 g (7.38 mmol, 17%) white powder.
MP: 110-112°C.
Rf-value: 0.53, thin layer chromatogram in silica gel, mobile phase/methanol/25 % ammonia 80:25:5.
Preparation of the starting compound: octadecyl-2-bromoethyl-phosphate: 62.5 g (0.50 mol) 2-bromoethanol are dissolved in 50 ml CHC13 and mixed dropwise at room temperature with 68.7 ml (0.75 mol) POC13. The mixture is heated under argon for 6 hours to 55°C and then left to stand over night. The product is then evaporated in a vacuum and the 2-bromoethylphosphorous oxydichloride formed is distilled in a high vacuum.
Yield: 68.0 g (281 mmol; 57%) 2-bromoethylphosphorous oxydichloride, boiling point 58-62°C (0.1 mbar). 44.4 g (0.164 mol) octadecanol and 60 g (0.249 mol) 2-bromoethy lphosphor ous oxydichloride are dissolved in 250 ml toluene and mixed dropwise with stirring with 19.8 ml (0.249 mol) pyridine. After stirring for 4 hours the mixture is evaporated, the residue mixed with 160 ml H2O and heated under reflux for 1.5 hours. The still hot suspension is poured onto 160 g ice to which 41.5 ml concentrated HCl had been added. The precipitating octadecyl-2-bromoethylphosphate is suction filtered and dried over P2O5.
Yield: 64.5 g (0.140 mmol, 86%) octadecyl-2bromoethylphosphate.
Example 3 Preparation of_octadecvl-Γ 2-(N-methvlpjperidino-ethvl1phosphate according to process b) Ethyleneoctadecylphosphate is dissolved in 600 ml acetonitrile and caused to react in an autoclave for 24 hours with 125 ml (1.03 mol) N-methylpiperidine at 80°C. After cooling the apparatus is opened and the brown reaction solution is placed in the ice compartment for crystallization purposes. After suction filtering and drying, 92 g (193 mmol, 61%) of reaction product are obtained. The crystals are stirred with acetone, dissolved in CH2C12 and chromatographed in silica gel with CHC13/methanol/25 percent NH4OH (60:40:4, then 80:25:5). The fractions containing the product are concentrated, the octadecyl- [2-N-methylpiperidino) -ethyl] -phosphate precipitating as a white solid after drying over P2O5 in a vacuum.
MP: 108 - 110°C Rf: 0.53, thin layer chromatogram on silica gel; mobile phase methylene chloride/methanol/25% aqueous ammonia 80:25:5 Yield: 18 g (37.8 mmol, 12%) The starting ethylene octadecyl phosphate is obtained for example as follows in this example: 85.3 G (315 mmol) octadecanol are dissolved under N2 in a dry stirring apparatus in 500 ml dry ether and mixed with 41 ml (345 mmol) freshly distilled N-methyIpiperidine. After cooling to 5°C a solution composed of 50 g (345 mmol) 2-chloro-2-oxo-l,3,2-dioxaphospholan in 170 ml dry ether at -10°C is added dropwise with exclusion of moisture within 30 minutes. When addition is completed the mixture is stirred at room temperature for one hour. The precipitated N-methylpiperidinium hydrochloride is suction filtered under a protecting gas and the filtrate is concentrated in a vacuum at a bath temperature of 30°C. Yield: 103 g (284 mmol, 90%) ethyleneoxtadecyl phosphate.
Example 4 Preparation of octadecvl-r2-(N-methvlpiperidino)-ethyl1phosphate according to process d), methylation. 3.7 g (8.00 mmol) octadecyl-2-piperidinoethylphosphate and 0.63 ml (10.0 mmol) methyliodide are dissolved in 20 ml acetonitrile and heated in an autoclave for 6 hours to 100°C. The mixture is cooled to room temperature, the resultant precipitate is suction filtered, dissolved in 140 ml 96 percent ethanol and stirred for 1.5 hours with 50 mg ion exchanger Amberlite* MB3. The mixture is evaporated after the ion exchanger has been filtered off. The residue is stirred with 20 ml butanone and dried in a vacuum at 40°C over P2O5.
Yield: 0.96 g (2.02 mmol) amorphous product D-20133.
The starting substance is for example obtained as follows: 27.3 g (60.0 mmol) octadecyl-2-bromoethyl phosphate are dissolved in 90 ml (900 mmol) piperidine and boiled under reflux for 1.5 hours. After cooling the result is evaporated, the residue is dissolved in 150 ml methanol, mixed with 25.2 g (90.0 mmol) Ag2CO3 and boiled for 1.5 hours. The result is suctioned off hot over a membrane filter and evaporated. The resultant black oil is chromatographed on silica gel with CHCl3/methanol/25 percent NH4OH (80:25:5). The fractions containing the octadecyl-2-piperidinoethyl phosphate are evaporated and the residue recrystallized from 200 ml butanone.
Yield: 13.2 g (28.6 mmol, 48%) Octadecy1-2-piperidinoethy1 phosphate.
Claims (15)
1. A medicament with anti-neoplastic effect containing octadecyl-(2-(N-methylpiperidino)-ethyl]-phosphate as active substance.
2. A process for the preparation of octadecyl-[2-(Nmethylpiperidino)-ethyl]-phosphate, characterized in that a) n-octadecyl alcohol is reacted with phosphorus oxychloride in a single vessel process optionally in the presence of an inert solvent, in the presence or absence of a basic substance, the product obtained is further reacted without isolation and purification in an inert solvent with an N-methyl-piperidino-ethanol salt in the presence of a basic substance to phosphoric acid diester chloride and the octadecyl-[2-(N-methylpiperidino)ethyl]-phosphate is liberated and isolated by subsequent hydrolysis or that b) a compound of formula c i8 H 37-°- po (° H ) 2 or a reactable derivative of this compound is reacted in a manner known per se with a compound of formula Z-H. II optionally in the presence of basic substances, where Z represents hydrogen, methyl or the group -CH 2 -CH 2 -OH and the piperidine compound may also be present in the form of the N-methyl-piperidinium derivative, where in this case the positive charge is neutralized by the anion of an inorganic or organic acid and optionally methylated, or c) a compound of the formula C 18 H 37 -O-PO ( OH )“°“ CH 2 CH 2 Y 111 where Y is chlorine, bromine or iodine is reacted with piperidine or N-methyl-piperidine and optionally 5 methylated or d) a compound of the general formula C 18 H 37° PO (° h ) “O-CH 2 -CH 2 -N IV is methylated or a compound obtained according to b) or c) is methylated.
3. A purification process for octadeeyl-[2-(N15 methylpiperidino)-ethyl]-phosphate, characterizedinthat a solution of octadecyl-[2-(N-methylpiperidino)ethyl]-phosphate prepared using a process known per se or using the process according to Claim 2 is treated in an organic agent with a mixed-bed ion exchanger, or 20 successively with an acid ion exchanger and a basic ion exchanger.
4. Octadecyl-[2-(N-methylpiperidino)-ethyl ]-phosphate for use as a therapeutically active substance.
5. A medicament containing octadecyl- [2- (N-methylpiperidino) ethyl]-phosphate as well as conventional carriers and/or diluents or auxiliary substances. 30
6. A process for the preparation of a medicament, characterized in that octadecyl-[2-(N-methylpiperidino)ethyl]-phosphate with conventional pharmaceutical carriers and/or diluents or other auxiliary substances is processed into pharmaceutical formulations or brought into a 35 therapeutically applicable form.
7. The use of octadecyl-[2-(N-methylpiperidino)-ethyl]25 phosphate for the preparation of medicaments.
8. A medicament according to Claim 1 or 5, substantially as hereinbefore described.
9. A process for the preparation of a medicament according to Claim 1 or 5, substantially as hereinbefore described.
10. A medicament according to Claim 1 or 5, whenever prepared by a process claimed in Claim 6 or 9.
11. A process according to Claim 2 for the preparation of octadecyl-[2-(N-methylpiperidino)-ethyl]-phosphate, substantially as hereinbefore described and exemplified.
12. Octadecyl-[2-(N-methylpiperidino)-ethyl]-phosphate, whenever prepared by a process claimed in Claim 2 or 11 .
13. A purification process according to Claim 3 for octadecyl-[2-(N-methylpiperidino)-ethyl]-phosphate, substantially as hereinbefore described and exemplified.
14. Purified octadecyl-[2-(N-methylpiperidino)-ethyl]-phosphate, whenever obtained by a process claimed in Claim 3 or 13.
15. Use according to Claim 7, substantially as hereinbefore described.
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| US8383605B2 (en) * | 2002-07-30 | 2013-02-26 | Aeterna Zentaris Gmbh | Use of alkylphosphocholines in combination with antimetabolites for the treatment of benign and malignant oncoses in humans and mammals |
| KR101378005B1 (en) * | 2005-12-19 | 2014-03-27 | 아에테르나 젠타리스 게엠베하 | Alkyl phospholipid derivatives with reduced cytotoxicity and uses thereof |
| US20070167408A1 (en) * | 2005-12-19 | 2007-07-19 | Zentaris Gmbh | Novel alkyl phospholipid derivatives with reduced cytotoxicity and uses thereof |
| JP5068630B2 (en) * | 2007-11-15 | 2012-11-07 | オルガノ株式会社 | Method for removing aldehyde compound from alcohol-containing solution and brewed sake purified by the method |
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| SG47844A1 (en) * | 1991-07-04 | 1998-04-17 | Asta Medica Ag | A process for the preparation of alkylphosphocholines and the production thereof in pure form |
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